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Intravenous endothelin-1 and ventilatory sensitivity to hypoxia in humans.
The effects of intravenous endothelin-1 (ET-1) on the ventilatory response to hypoxia were studied in healthy humans. Nine volunteers were each exposed twice to 4 hr eucapnic hypoxia. They received a continuous infusion of ET-1 during the ET-1 protocol and an infusion of saline during the control protocol. Plasma ET-1 levels and an index of ventilation were measured regularly. Hypoxia caused a rise in plasma ET-1 in the control protocol. Hypoxia also caused the index of ventilation to increase in both protocols, and this increase was greater in the ET-1 protocol than in the control protocol. These results are consistent with the hypothesis that ET-1 plays a role in controlling the ventilatory response to hypoxia in man.
The obligatory role of the kidney in long-term arterial blood pressure control: extending Guyton's model of the circulation.
We describe a model for the essential role of the kidney in long-term blood pressure regulation. We begin with a simple hydraulic model for the circulation, with a constant circulating volume. We show, with the help of a modification of Guyton's classic diagram, that cardiac output and mean arterial pressure are functions of circulating volume, peripheral resistance, venous and arterial compliances, and the cardiac Starling curve. This approach models only acute changes in a 'closed' circulation--one where there is no intake or excretion of fluid. The model is then adapted to 'open' the circulation, include a role for the kidney, and represent more chronic changes. Arterial pressure is then a sole function of renal behaviour and daily sodium (and liquid) intake, and becomes independent of other cardiovascular variables. As well as generating specific hypotheses for further investigation, these models can be used for the purpose of education in cardiovascular control and the treatment of hypertension.
Can intravenous endothelin-1 be used to enhance hypoxic pulmonary vasoconstriction in healthy humans?
BACKGROUND: Hypoxic pulmonary vasoconstriction (HPV) helps match pulmonary perfusion to ventilation. The peptide endothelin-1 (ET-1) may be involved in the cellular mechanisms of this response. We hypothesized that increasing plasma ET-1 concentration during hypoxia would enhance HPV in humans and might represent a strategy for improving gas exchange during single-lung anaesthesia or respiratory disease. METHODS: Nine healthy volunteers were each exposed twice to a 7-h protocol consisting of 1 h breathing air, 4 h of eucapnic hypoxia (end-tidal Po(2), 50 mm Hg), and 2 h of eucapnic euoxia (end-tidal Po(2), 100 mm Hg). Volunteers received a 7-h i.v. infusion of ET-1 during one protocol (1.0-2.5 ng kg(-1) min(-1)) and normal saline during the other. At intervals of 30-60 min, cardiac output and the maximum tricuspid pressure gradient during systole (DeltaP(max), an index of HPV) were measured using Doppler echocardiography, systemic arterial pressure was measured using sphygmomanometry, and plasma samples were obtained to determine ET-1 concentration. RESULTS: During hypoxia, DeltaP(max) increased for around 2 h before reaching a plateau. Compared with saline, ET-1 had no effect on DeltaP(max), either at baseline or during hypoxia. ET-1 infusion slightly increased diastolic arterial pressure and reduced cardiac output, but had no specific effect on the change in these variables during hypoxia. During the final 1 h of hypoxia, plasma ET-1 concentration was 1.7 (0.4) pg ml(-1) [mean (sd)] in the saline protocol and 21.9 (12.2) pg ml(-1) in the ET-1 protocol. CONCLUSIONS: ET-1 infusion seems unlikely to represent a therapeutic strategy for enhancing HPV during acute (<4 h) hypoxia.
End-tidal sevoflurane and halothane concentrations during simulated airway occlusion in healthy humans.
BACKGROUND: In a patient whose airway is likely to become obstructed upon loss of consciousness, anesthesia may be induced using an inhaled vapor. If the airway occludes during such an inhalational induction, the speed of patient awakening is related to the rate at which anesthetic gas redistributes away from lung and brain to other body compartments. To determine whether redistribution occurs more rapidly with a more blood-soluble or a less blood-soluble agent, the authors used subanesthetic concentrations of halothane and sevoflurane to simulate inhalational induction and airway obstruction in eight healthy human volunteers. METHODS: Inhalational induction was simulated using stepwise increases in inspired halothane or sevoflurane concentration, sufficient to reach an end-tidal concentration of approximately 0.1 minimal alveolar concentration. Airway occlusion was then simulated by initiating a 90-s period of rebreathing from a 1-l bag. During rebreathing, end-tidal halothane or sevoflurane concentration was measured continuously by mass spectrometry, and a time constant for the decline in concentration was calculated using a monoexponential model. RESULTS: At the onset of rebreathing, end-tidal concentrations of halothane and sevoflurane were 0.10 +/- 0.03 and 0.11 +/- 0.03 minimal alveolar concentration, respectively (mean +/- SD; P > 0.1, Student t test). During rebreathing, the time constants for the decline in end-tidal halothane and sevoflurane concentration were 22 +/- 9 and 62 +/- 16 s, respectively (P < 0.0001). CONCLUSIONS: During simulated airway occlusion in healthy volunteers, the end-tidal concentration of halothane falls more rapidly than that of sevoflurane. Halothane may therefore lead to more rapid awakening, compared with sevoflurane, should the airway obstruct during an inhalational induction of anesthesia.
Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha gain-of-function mutation.
The hypoxia-inducible factors (HIFs; isoforms HIF-1α, HIF-2α, HIF-3α) mediate many responses to hypoxia. Their regulation is principally by oxygen-dependent degradation, which is initiated by hydroxylation of specific proline residues followed by binding of von Hippel-Lindau (VHL) protein. Chuvash polycythemia is a disorder with elevated HIF. It arises through germline homozygosity for hypomorphic VHL alleles and has a phenotype of hematological, cardiopulmonary, and metabolic abnormalities. This study explores the phenotype of two other HIF pathway diseases: classic VHL disease and HIF-2α gain-of-function mutation. No cardiopulmonary abnormalities were detected in classic VHL disease. HIF-2α gain-of-function mutations were associated with pulmonary hypertension, increased cardiac output, increased heart rate, and increased pulmonary ventilation relative to metabolism. Comparison of the HIF-2α gain-of-function responses with data from studies of Chuvash polycythemia suggested that other aspects of the Chuvash phenotype were diminished or absent. In classic VHL disease, patients are germline heterozygous for mutations in VHL, and the present results suggest that a single wild-type allele for VHL is sufficient to maintain normal cardiopulmonary function. The HIF-2α gain-of-function phenotype may be more limited than the Chuvash phenotype either because HIF-1α is not elevated in the former condition, or because other HIF-independent functions of VHL are perturbed in Chuvash polycythemia.
Extent to which pulmonary vascular responses to PCO2 and PO2 play a functional role within the healthy human lung.
Regional blood flow in the lung is known to be influenced by the alveolar PCO2 and alveolar PO2. For the healthy lung, the extent to which this influence is of functional importance in limiting heterogeneity in alveolar gas composition by matching regional perfusion (q) to regional ventilation (v) remains unclear. To address this issue, the efficiency of regulation (E) was defined as the percent correction to an initial perturbation in regional alveolar gas composition generated by the pulmonary vascular response to the disturbance. This study develops the theory to calculate E from global measurements of vascular reactivity to CO2 and O2 in human volunteers. For O2, these data were available from the literature. For CO2, an experimental component of the present study used Doppler echocardiography to evaluate the magnitude of the global vascular response to hypercapnia and hypocapnia in 12 volunteers over a timescale of approximately 0.5 h. The results suggest a value for E of approximately 60% over a wide range of values for v-to-q ratio (approximately 0.1-10) encompassing those found in normal lung. At low v/q (<0.65), the vascular response to O2 forms the dominant mechanism; however, at higher v/q (>0.65), the response to CO2 dominates. The values for E suggest that the pulmonary vascular responses to both CO2 and O2 play a significant role in ventilation-perfusion matching in the healthy human lung.
Effects of hydralazine on the pulmonary vasculature and respiratory control in humans.
This study sought: (1) to clarify the effects of hydralazine on both the pulmonary vasculature and respiratory control in euoxia and hypoxia in healthy humans; and (2) to determine whether hydralazine alters the expression of genes regulated by hypoxia-inducible factor 1 (HIF-1). Ten volunteers participated in two 2 day protocols. Hydralazine (25 mg) or placebo was administered at 1 pm and 11 pm on the first day, and at 1 pm on the second day. In the mornings and afternoons of both days, we measured plasma vascular endothelial growth factor (VEGF) and erythropoietin (EPO) concentrations (both HIF-1-regulated gene products), systemic arterial blood pressure, and changes in heart rate, cardiac output, maximal systolic pressure difference across the tricuspid valve (delta Pmax) and ventilation in response to 20 min of isocapnic hypoxia. Recent hydralazine: (1) decreased diastolic blood pressure; (2) increased heart rate and cardiac output in euoxia and hypoxia whilst having no effect on delta Pmax; and (3) increased the ventilatory sensitivity to hypoxia. Hydralazine had no effect on plasma EPO or VEGF concentration. We conclude that hydralazine increases the sensitivity of the ventilatory response to hypoxia, but lacks any effect on the pulmonary vasculature at the dose studied. It did not affect the expression of HIF-1-regulated genes.
Separating the direct effect of hypoxia from the indirect effect of changes in cardiac output on the maximum pressure difference across the tricuspid valve in healthy humans.
In healthy humans, changes in cardiac output are commonly accommodated with minimal change in pulmonary artery pressure. Conversely, exposure to hypoxia is associated with substantial increases in pulmonary artery pressure. In this study we used non-invasive measurement of an index of pulmonary artery pressure, the maximum systolic pressure difference across the tricuspid valve (DeltaPmax), to examine the pulmonary vascular response to changes in blood flow during both air breathing and hypoxia. We used Doppler echocardiography in 33 resting healthy humans breathing air over 6-24 h to measure spontaneous diurnal variations in DeltaPmax and cardiac output. Cardiac output varied by up to approximately 2.5 l/min; DeltaPmax varied little with cardiac output [0.61+/-0.74 (SD) mmHg min l(-1)]. Eight of the volunteers were also exposed to eucapnic hypoxia (end-tidal PO2 = 50 mmHg) for 8 h. In this group DeltaPmax rose progressively from 21 mmHg to 37 mmHg over 8 h. By comparing diurnal variations in DeltaPmax during air breathing with changes in DeltaPmax during hypoxia in the same eight individuals, we concluded that only approximately 5% of the changes in DeltaPmax during hypoxia could be attributed to concurrent changes in cardiac output. The low sensitivity of DeltaPmax to changes in cardiac output makes it a useful index of hypoxic pulmonary vasoconstriction in healthy humans.
Effects of subanaesthetic sevoflurane on ventilation. 2: Response to acute and sustained hypoxia in humans.
We have determined the influence of 0.1 minimum alveolar concentration (MAC) of sevoflurane on the acute ventilatory response to hypoxia (AHVR), hypoxic ventilatory decline (HVD) and the magnitude of the rapid decline in ventilation on relief of sustained hypoxia (the off-response) in eight healthy adult volunteers. The following design was used with and without 0.1 MAC of sevoflurane: end-tidal PO2 was maintained at 13.3 kPa for 5 min, at 7.9 kPa for 20 min and at 13.3 kPa for 5 min. End-tidal PCO2 was held constant throughout at 1.3 kPa above the subject's normal value. A dynamic end-tidal forcing system was used to generate these gas changes. Sevoflurane reduced AHVR from 14.5 (SEM 1.2) to 11.6 (1.6) litre min-1, and the off-response at cessation of hypoxia from 7.1 (1.1) to 6.3 (1.4) litre min-1. The magnitude of HVD was slightly increased by sevoflurane from 8.2 (1.1) to 10.6 (2.8) litre min-1. None of these changes was significant (ANOVA). These results suggest that 0.1 MAC of sevoflurane had very little effect on the AHVR, and that it did not markedly alter the processes underlying HVD during sustained hypoxia.
Effects of subanaesthetic sevoflurane on ventilation. 1: Response to acute and sustained hypercapnia in humans.
We have determined the influence of 0.1 minimum alveolar concentration (MAC) of sevoflurane on ventilation, the acute ventilatory response to a step change in end-tidal carbon dioxide and the ventilatory response to sustained hypercapnia in 10 healthy adult volunteers. Subjects undertook a preliminary 10-min period of breathing air without sevoflurane to determine their normal ventilation and natural end-tidal PCO2. This 10-min period was repeated while breathing 0.1 MAC of sevoflurane. Subjects then undertook two procedures: end-tidal PO2 was maintained at 13.3 kPa and end-tidal PCO2 at 1.3 kPa above the subject's normal value for 30 min of data collection, first with and then without 0.1 MAC of sevoflurane. A dynamic end-tidal forcing system was used to generate these gas profiles. Sevoflurane did not significantly change ventilation: 10.1 (SEM 1.0) litre min-1 without sevoflurane, 9.6 (0.9) litre min-1 with sevoflurane. The response to acute hypercapnia was also unchanged: mean carbon dioxide response slopes were 20.2 (2.7) litre min-1 kPa-1 without sevoflurane and 18.8 (2.7) litre min-1 kPa-1 with sevoflurane. Sustained hypercapnia caused a significant gradual increase in ventilation and tidal volume over time and significant gradual reduction in inspiratory and expiratory times. Sevoflurane did not affect these trends during sustained hypercapnia. These results suggest that 0.1 MAC of sevoflurane does not significantly affect the acute ventilatory response to hypercapnia and does not modify the progressive changes in ventilation and pattern of breathing that occur with sustained hypercapnia.
Pulmonary artery pressure increases during commercial air travel in healthy passengers.
BACKGROUND: It is not known whether the mild hypoxia experienced by passengers during commercial air travel triggers hypoxic pulmonary vasoconstriction and increases pulmonary artery pressure in flight. Insidious pulmonary hypertensive responses could endanger susceptible passengers who have cardiopulmonary disease or increased hypoxic pulmonary vascular sensitivity. Understanding these effects may improve pre-flight assessment of fitness-to-fly and reduce in-flight morbidity and mortality. METHODS: Eight healthy volunteers were studied during a scheduled commercial airline flight from London, UK, to Denver, CO. The aircraft was a Boeing 777 and the duration of the flight was 9 h. Systolic pulmonary artery pressure (sPAP) was assessed by portable Doppler echocardiography during the flight and over the following week in Denver, where the altitude (5280 ft/1610 m) simulates a commercial airliner environment. RESULTS: Cruising cabin altitude ranged between 5840 and 7170 ft (1780 to 2185 m), and mean arterial oxygen saturation was 95 +/- 0.6% during the flight. Mean sPAP increased significantly in flight by 6 +/- 1 mmHg to 33 +/- 1 mmHg, an increase of approximately 20%. After landing in Denver, sPAP was still 3 +/- 1 mmHg higher than baseline and remained elevated at 30 +/- 1 mmHg for a further 12 h. CONCLUSIONS: Pulmonary artery pressure increases during commercial air travel in healthy passengers, raising the possibility that hypoxic pulmonary hypertension could develop in susceptible individuals. A hypoxia altitude simulation test with simultaneous echocardiography ('HAST-echo') may be beneficial in assessing fitness to fly in vulnerable patients.
The first intravenous anaesthetic: how well was it managed and its potential realized?
Our speciality commonly traces its origin to a demonstration of the inhalation of ether by a patient undergoing surgery in Boston in 1846. Less well known is the demonstration of the i.v. injection of opium with alcohol into a dog in Oxford in 1656, leading to anaesthesia followed by full long-term recovery. After gaining i.v. access, a mixture of opium and alcohol was injected, resulting in a brief period of anaesthesia. After a period during which the dog was kept moving to assist recovery, a full recovery was made. Details from this momentous experiment allow us to compare the technique used with modern management. It is important to consider why there was a failure to translate the results into clinical practice and nearly 200 yr of potentially pain-free surgery. Possible factors include lack of equipment for i.v. access, lack of understanding of dose-response effects, and a climate of scientific discovery rather than clinical application. Given the current interest in total i.v. anaesthesia, it seems appropriate to identify its origins well before those of inhalation anaesthesia.